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AOP: 260

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

CYP2E1 activation and formation of protein adducts leading to neurodegeneration

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
CYP2E1 activation and formation of protein adducts leading to neurodegeneration

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Jelle Broeders   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Jelle Broeders
  • Marvin Martens

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Handbook Version OECD status OECD project
v2.0
This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page Revision Date/Time
CYP2E1 Activation April 09, 2018 11:02
Protein Adduct Formation March 26, 2018 09:45
Oxidative Stress in Brain April 04, 2018 14:24
Lipid Peroxidation April 04, 2018 14:33
Unfolded Protein Response September 14, 2023 08:51
General Apoptosis October 18, 2023 12:20
Neurodegeneration April 04, 2018 14:53
CYP2E1 Activation leads to Oxidative Stress in Brain April 05, 2018 03:40
Oxidative Stress in Brain leads to Lipid Peroxidation April 05, 2018 04:06
Lipid Peroxidation leads to Protein Adduct Formation April 05, 2018 04:18
Protein Adduct Formation leads to Unfolded Protein Response April 05, 2018 04:25
Oxidative Stress in Brain leads to Unfolded Protein Response April 05, 2018 04:37
Lipid Peroxidation leads to General Apoptosis April 05, 2018 04:48
Unfolded Protein Response leads to General Apoptosis April 05, 2018 04:51
General Apoptosis leads to Neurodegeneration April 05, 2018 04:53
Acetaminophen November 29, 2016 18:42
Enflurane April 05, 2018 06:31
Halothane April 05, 2018 06:32
Isoflurane April 05, 2018 06:32
Methoxyflurane April 05, 2018 06:32
Sevoflurane April 05, 2018 06:33
Chemical:584015 (1-~13~C)Aniline April 05, 2018 06:33
Chlorzoxazone April 05, 2018 06:34
Titanium oxide (TiO) April 05, 2018 06:35
Isoniazid April 05, 2018 06:36
Ethanol April 05, 2018 06:38

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The AOP has two different MIEs: protein adduct formation (MIEa) and CYP2E1 activation (MIEb). Protein adduct formation is the interaction between a chemical, or reactive metabolite, and a protein at molecular level. During this interaction a covalent bond is formed which occurs due to the reaction between an electrophilic chemical and the nucleophilic part of a protein. When a chemical forms a covalent bond with a protein the protein is damaged and can loses its function. Acetaldehyde, the metabolite of ethanol, is also one of these chemicals known to form protein adducts. This is why protein adduct formation is added in this AOP based on ethanol. CYP2E1 is one of the enzymes responsible for the metabolism of ethanol, and because of this metabolic activity the MIE in added in this AOP. CYP2E1 participates in the metabolism of endogenous, small and hydrophobic compounds using a oxidation reaction. CYP2E1 is mainly expressed in rat liver cells, but can also be found in rat brain cells. Furthermore, in the human brain CYP2E1 expression is mainly found in the amygdala and prefrontal cortex. At higher concentrations of ethanol the expression of CYP2E1 increases, as well as the activity of CYP2E1 since it has a relatively high Km value for ethanol. In this AOP four different KEs are used, which are oxidative stress (KE1), lipid peroxidation (KE2), unfolded protein response (UPR) (KE3) and apoptosis (KE4). Oxidative stress can be defined as the imbalance between ROS and defence mechanisms against these ROS. ROS levels in a cell can rise which leads to damage by the oxidizing free radicals. Lipid peroxidation is a form of direct damage to lipids in the cell membrane or organelle membranes. The cell membrane will eventually break due to the build-up of all the damage. MDA  and 4-hydroxynonenal (HNE) are two products of lipid peroxidation. UPR is a reaction activated by stress in the endoplasmic reticulum (ER). ER stress can be induced by too much protein folding which reaches a higher level than the folding capacity. Also accumulation of unfolded protein in the ER and protein adducts formation with important endoplasmic proteins can induce ER stress, which activates UPR. The final KE is apoptosis, which is programmed cell death in general. The process of apoptosis is well regulated and several signal proteins are known to induce the apoptotic process.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1508 CYP2E1 Activation CYP2E1 Activation
MIE 1509 Protein Adduct Formation Protein Adduct Formation
KE 1510 Oxidative Stress in Brain Oxidative Stress in Brain
KE 1511 Lipid Peroxidation Lipid Peroxidation
KE 1512 Unfolded Protein Response Unfolded Protein Response
KE 1513 General Apoptosis General Apoptosis
AO 1514 Neurodegeneration Neurodegeneration

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Key Event

Essentiality

MIEa (Protein Adduct Formation)

Moderate support. Activation of MIEa induces increased activation of KE 3, but direct evidence is not available. One theory about the mechanism is that adducts are formed with critical ER proteins. (Haberzettl, P. & Hill, B. G., 2013; Galligan, J. J. et al., 2014; Cumaoglu, A. et al., 2014; Kessova, I. G. & Cederbaum, A. I., 2005; Huličiak, M. et al., 2012; Sadrieh, N. & Thomas, P. E., 1994; Shin, N. Y. et al., 2007; Sapkota, M. & Wyatt, T. A., 2015; Tuma, D. J., 2002)

MIEb (CYP2E1 Activation)

High support. Direct evidence is available which prevents the upstream KE 1. CYP2E1 knockout as well as inhibition studies are performed. Activation of CYP2E1 by stressors also showed an increased. (Valencia-Olvera, A. C. et al., 2014; Haorah, J. et al, 2008; Luo, J., 2014; Yang, L. & Cederbaum, A., 2011; Lakshman, M. R. et al., 2013; Jimenez-Lopez, J. M. & Cederbaum, A. I., 2005; Gonzalez, F. J., 2005; Albano, E. et al., 1996; Albano, E., 2006; Wu, D. et al., 2012; Cederbaum, A. I., 2010; Lu, Y. et al., 2010; Oneta, C. M. et al., 2002; Lieber, C. S., 2004; Emerit, J. et al., 2004)

KE 1 (Oxidative Stress)

High support. Direct and indirect evidence is available for the essentiality of KE 1. Blocking ROS formation inhibits upstream KE 2 and KE 3. The indirect evidence showed that higher ROS induction showed an increased activity of upstream KE 2 and KE 3.

KE 2 (Lipid Peroxidation)

High support. There is much indirect evidence available showing that inducement of lipid peroxidation can increase activity of MIEb and KE 4. The direct evidence of blocking HNE which results in inhibition of upstream KE 4 shows that there is link between KE 2 and KE 4 and that the underlying molecular pathway is known.

KE 3 (UPR)

Moderate support. There is direct as well as indirect evidence available which shows molecular understanding of how KE 3 can induce KE 4. The uncertainty lies in whether ER stress alone can induce KE 4, or that KE 1 also plays a role in it. This is more discussed in detail in chapter 4.

KE 4 (Apoptosis)

High support. Neurodegeneration is the loss of neuron cells in the brain.

See table below where an overview is provided of the direct and indirect evidence. For the meaning of numbering see Abstract and the image of the AOP,

Key event relatio-nship

Methods

Influence on downstream Key events

Direct/Indirect evidence

KER 1: MIEb ---> KE1

1. Stimulation of CYP2E1 by stressors in rat livers.

2. Inhibition studies of CYP2E1 in neuron cells.

3. CYP2E1 KO in mice where TBARS values are measured.

4. Induction of CYP2E1 results in higher ROS levels an higher CYP2E1 expression, study performed in granule neuron cells.

1. Activation KE 1

2. Inhibition KE 1

3. Inhibition KE 1

4. Activation KE 1

1. Indirect

2. Direct

3. Direct

4. Indirect

KER 2: KE1 ---> KE2

1. Lower ROS level by adding higher concentrations of antioxidants or resveratrol (inhibitor of ROS). TBARS and LOOH product was measured in rat microsomes.

2. Correlation study where higher ROS levels increased lipid peroxidation in aging brains.

1. Inhibition KE 2

2. Activation KE 2

1. Direct

2. Indirect

KER 3: KE1 ---> KE3

1. Lower ROS levels by overexpression of antioxidant SOD1, NAC or GSH resulted in induction of UPR markers. Measured in neuron cells.

2. Stimulation of ROS formation by ethanol, which induces the UPR response in 2 hours after exposure.

1. Inhibition KE 3

2. Activation KE 3

1. Direct

2. Indirect

KER 4: KE2 ---> MIEa

1.Proteomic detection techniques for HNE adducts, HNE is a reactive aldehyde product of lipid peroxidation.

2. SERS monitoring detection, showed link between increased lipid peroxidation and increased protein adduct formation.

1. Activation MIEb

2. Activation MIEb

1. Indirect

2. Indirect

KER 5: MIEa ---> KE3

1. HNE (known to form protein adducts) treatment in rat aortic smooth muscle cells induced expression of the PERK pathway, which is part of the UPR. Same study is also performed in different settings.

2. Some toxicants can form protein adducts with ER proteins, what can induce ER stress and the UPR.

1. Activation KE 3

2. Activation KE 3

1. Indirect

2. Indirect

KER 6: KE2 ---> KE4

1. HNE can induce Fas/CD95DR expression, which regulated the extrinsic pathway of apoptosis.

2. Knockout of GSTA4 in mouse, which is an antioxidant for HNE, showed an increase in Fas expression.

3. ASK1 and JNK are activated by Fas. Increased HNE concentrations showed higher expression of ASK1 and JNK. When Fas was inhibited apoptosis was stopped.

4. HNE induces mitochondrial dysfunction which leads to apoptosis. Higher HNE levels showed increased expression of cytochrome c and caspases. Caspase 3 and 9 are mainly activated. Both are part of the intrinsic pathway of apoptosis.

1. Activation KE 4

2. Inhibition KE 4

3. Activation KE 4

4. Activation KE 4

1. Indirect

2. Direct

3. Indirect

4. Indirect

KER 7: KE3 ---> KE4

1. Higher expression of IRE1 and PERK, which are UPR markers, showed an increase of caspases expression. These caspases play a major role in the apoptotic pathway.

2. Inhibition of ER stress by DHCR24 resulted in a lower level of CHOP expression. Also an inhibition of apoptosis was shown.

1. Activation KE 4

2. Inhibition KE 4

1. Indirect

2. Direct

KER 8: KE4 ---> AO

1. Neuron loss is detected in neurodegenerative diseases, such as Alzheimer.

1. Activation AO

1. Indirect

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

In AOP1 there are some knowledge gaps present which is one of the principles of the AOP concept. CYP2E1 activation is known to increase the ROS concentration in a cell, but the underlying mechanism is not completely understood. There are two main mechanisms which are suggested in literature, either CYP2E1 or NADPH oxidase could be the primary enzyme which is responsible for ROS formation and cause the further damage in the cells. NAPDH oxidase recycles the NADP+ which is formed during the reaction cycle of CYP2E1, during this cycle ROS is formed due to the uncoupling reaction. CYP2E1 shows a relatively high activity of NADPH oxidase activity and is poorly coupled with NADPH-cytochrome P450 reductase. When NADPH oxidase is inhibited by anti-CYP2E1 IgG a reduction of ROS induced lipid peroxidation was shown. Knock-out or inhibition of CYP2E1 itself resulted in lower oxidative stress. A study performed by Bradford et al. showed that NADPH oxidase knock-out mice attenuated liver injury, where CYP2E1 knock-out mice did not show attenuating of liver injury. On the other hand, NADHP oxidase knock-out mice did not reduce oxidative stress damage to DNA, where CYP2E1 knock-out mice did reduced the damage. Another study by Zhang et al. looked at the influence of NADPH oxidase, an inhibiter against NADPH oxidase was used which reduced the formation of ROS in PC12 cells. Finally, Shah et al. and Furukawa et al. also showed that NADPH oxidase inhibition leads to a reduced formation of ROS, both studies were done in different disease context. The principle of ROS formation by NADPH oxidase is the formation of H2O2 since O2 is used as a substrate. By the Fenton-Weiss-Haber reaction multiple oxidants can be produces. But as mentioned above, several studies showed that CYP2E1 inhibition alone is enough to reduce ROS formation. To take into account, studies described above are all done in liver cells. The mechanism of CYP2E1 activation could be different in the brain.

Another knowledge gap is the mechanism of protein adducts that can induce ER stress, and ultimately the UPR. The assumed mechanism is that protein adducts are formed with critical ER proteins, which leads to the dysfunction of the ER. Furthermore, it is also a possibility that protein adducts inhibit the folding of proteins. These proteins can accumulate in the ER and when the protein accumulation is higher than the capacity ER stress is induced. Further research must be done to define the mechanism of how ER stress is induced by protein adducts, which will eventually lead to the UPR.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

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Haorah, J. et al. Mechanism of alcohol-induced oxidative stress and neuronal injury. Free Radic. Biol. Med. 45, 1542–1550 (2008).

Sapkota, M. & Wyatt, T. A. Alcohol, aldehydes, adducts and airways. Biomolecules 5, 2987–3008 (2015).

Tuma, D. J. Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radical Biology and Medicine 32, 303–308 (2002).

Valencia-Olvera, A. C., Morán, J., Camacho-Carranza, R., Prospéro-García, O. & Espinosa-Aguirre, J. J. CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons. Toxicol. Vitr. 28, 1206–1214 (2014).

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